A phase-I trial of the epidermal growth factor receptor directed bispecific antibody MDX-447 without and with recombinant human granulocyte-colony stimulating factor in patients with advanced solid tumors.
Cancer Immunol Immunother. 2007 Jun 30
Fury MG, Lipton A, Smith KM, Winston CB, Pfister DG.
Division of Solid Tumor Oncology, Head and Neck Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021, USA, pfisterd@mskcc.org.
INTRODUCTION:
MDX-447 is a bispecific antibody directed against the epidermal growth factor receptor (EGFR) and the high affinity Fc receptor (FcgammaRI). Preclinical data suggest that co-administration of granulocyte-colony stimulating factor (G-CSF) may enhance the tumor cytotoxicity of bispecific antibodies.
METHODS:
In group 1, patients received MDX-447 intravenously (IV) weekly. Dose levels of MDX-447 evaluated in group 1 were 1, 3.5, 7, 10, 15, 20, 30, and 40 mg/m(2). In group 2, patients received MDX-447 IV weekly with G-CSF (3 mcg/kg/day) subcutaneously (days -3 to +2, 5-9, 12-16, etc.). Dose levels of MDX-447 evaluated in group 2 were 1, 3.5, 7, 10, and 15 mg/m(2).
RESULTS:
Sixty-four patients with advanced solid tumors were treated. Forty-one patients received MDX-447 alone (group 1); 23 patients received MDX-447 + G-CSF (group 2). Hypotension was the predominant dose-limiting toxicity (DLT) in both treatment groups, with seven patients experiencing >/=grade 3 events. MDX-447 half-life (T(1/2)) ranged from 1.9 to 8.4 h, with no obvious differences between the two treatment groups. MDX-447 binding to neutrophils and peak levels of circulating tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) were higher in group 2. The MTD for MDX-447 alone was 30 mg/m(2). When G-CSF was given with MDX-447, treatment was not well tolerated and group 2 was closed early because of safety concerns, with the last patient being treated at the 7 mg/m(2) dose level. There were no objective complete or partial responses in either group.
CONCLUSION:
MDX-447 alone was generally well tolerated, but did not achieve objective tumor responses. The MTD for MDX-447 alone was 30 mg/m(2) weekly. Co-administration of G-CSF with MDX-447 precluded meaningful dose escalation. |
